THE AMAZING HEMOGLOBIN MOLECULE

THE AMAZING HEMOGLOBIN MOLECULE

https://reasonandscience.catsboard.com/t1322-the-amazing-hemoglobin-molecule

The most ancient heme domain is the globin-like fold and was certainly present in LUCA, the Last Universal Common Ancestor. 2

The argument by hemoglobin
1. The hemoglobin is a protein made of 564 amino acids.
2. The hemoglobin’s three-dimensional structure; the amino acid sequence and the 4 iron atoms in the central region of the hemoglobin are all together enabling the special function of the hemoglobin - the transfer of the oxygen.
3. An alteration of any part of this structure of hemoglobin would cause inability to execute its duty of carrying oxygen.
4. Conclusively, such a structure is a proof of perfect design.
5. Behind a design, there is an intelligent designer.
6. That designer is God.

Technological Ingenuity in Red Blood Cells 1

Each mm3 (= 1 ul = 1 microliter) of our blood contains five million red blood cells; so there are 150 million of them in each drop of blood. These highly specialized cells perform functions vital to life.
• Throughout their 120-day lifetime, while circulating through the lungs, they are refueled with oxygen 175,000 times, while simultaneously offloading carbon dioxide, the waste product of oxidation.
• Red blood cells are so tiny that they can squeeze through narrow capillaries to reach every part of the body.
• Our body produces two million new red cells every second and each cell is rich in hemoglobin, a remarkably complex chemical compound.

Hemoglobin is used for transporting oxygen, even during development of the embryo. Up to about the third month of pregnancy, the embryo's oxygen needs are distinctly different from those in the ensuing fetal stage, which are different again from the needs of the infant and adult. All three stages— embryo, fetus, and adult—require the production of chemically different forms of hemoglobin. Shortly before birth, for example, the body's 'factories' start switching to top production mode of the third (adult) type of hemoglobin. These three types of hemoglobin could not have arisen by trial-and-error evolutionary processes because none of the other mutant forms of the hemoglobin molecule could carry enough oxygen and would thus be deadly. Even if the right forms of hemoglobin were to somehow arise to supply the first two stages, but without the genetic coding to produce the third form, the outcome would still be certain death. Each of these three stages of our development requires fundamentally different DNA coding to produce each of the three different hemoglobin molecules.
Further, each set of different DNA coding and its biomachinery that synthesizes the hemoglobin molecules must be switched on and off at the right point in time. Where did such a complex system of information-controlled machinery come from? All conceivable evolutionary explanations fail miserably because any partially completed transitional stage required by evolution would not permit the organism to survive. The whole complex of
information and machinery must be present and functional from the start. This concept of 'irreducible complexity' also applies to the immune system and to the flagellum that many bacteria use to propel themselves. In each case, the organisms 'on the way' to their completed state would not have been able to survive. A more obvious explanation is that this information-controlled machinery was initially complete—something only possible if a wise Creator conceived and made everything fully functional in the beginning.

The heme biosynthesis pathway is irreducible complex.

Heme biosynthesis is a complex pathway with 8 highly specific steps, of which 6 steps are used by specific enzymes uniquely in this pathway.
The pathway must go all the way through, otherwise, heme is not synthesized.
Therefore, the heme biosynthesis pathway is irreducibly complex.

Questions: 
What good would there be, if the pathway would go only up to the 7th step? none
What good would there be, if the pathway would go all the way through the 8th step? Heme would be produced, BUT :
What good for survival would there be for Heme by its own, if not fully embedded in the globin proteins? none.
What good would there be for red blood cells without hemoglobin, transporting oxygen to the cells in the body? none, transporting oxygen is essential for the whole process. I conclude therefore that the heme biosynthesis pathway is irreducibly complex, and could not have evolved upon mutation and natural selection.

I mentioned that some enzymes have to be imported into the mitochondrion. These enzymes contain special protein sequences called targeting signals that direct them to the right place. So the next question: is globin targeted to the mitochondrion? No - it is synthesized on ribosomes, attached to the Golgi apparatus in the cytoplasm and it stays there. Some of the haem made in the mitochondrion is used by mitochondrial proteins called cytochromes, but the rest is exported back outside where it can attach to the globin protein. Have a look at these Wikipedia pages: heme and porphyrin, for some more details. Porphyrins, by the way, are intermediates in haem synthesis that also have the tetrapyrrole structure.

Researchers have done experiments in which they synthesized globin protein chains to see at what point the haem attached. It can attach when about 80-90 amino acids have emerged from the ribosome - in other words, it attaches to the "nascent chain" as the protein is being synthesized. One of the mysteries that we don't fully understand is how the hemoglobin assembles itself properly - so as it has 2 alpha chains and 2 beta chains each with a hemoglobin attached.

Question: for what reason would evolution try to assemble the heme to the globin? what survival advantage would there be provided by a globin without the heme? and what advantage of the heme without the globin?




Dr. Kofahl, a chemist, observes:

‘A good example of alleged molecular homology is afforded by the a- and b-hemoglobin molecules of land vertebrates including man. These supposedly are homologous with an ancestral myoglobin molecule similar to human myoglobin. Two a- and two b-hemoglobin associate together to form the marvelous human hemoglobin molecule that carries oxygen and carbon dioxide in our blood. But myoglobin acts as single molecules to transport oxygen in our muscles. Supposedly, the ancient original myoglobin molecules slowly evolved along two paths until the precisely designed a- and b-hemoglobin molecules resulted in that function only when linked together in groups of four to work in the blood in a much different way under very different conditions from myoglobin in the muscle cells. What we have today in modern myoglobin and hemoglobin molecules are marvels of perfect designs for special, highly demanding tasks. Is there any evidence that intermediate, half-evolved molecules could have served useful functions during this imaginary evolutionary change process, or that any creature could survive with them in its blood? There is no such information. Modern vertebrates can tolerate very little variation in these molecules. Thus, the supposed evolutionary history of the allegedly homologous globin molecules is a fantasy, not science.’

https://www.awesomestories.com/asset/view/Breathing-How-Oxygen-Travels-in-the-Body0



http://reasonandscience.heavenforum.org/post?p=1859&mode=editpost


http://creationsmarvels.blogspot.com.br/2013/02/the-amazing-hemoglobin-molecule-miracle.html

“Breathing seems so simple, yet it appears as if this elementary manifestation of life owes its existence to the interplay of many kinds of atoms in a giant molecule of vast complexity.”

Max F. Perutz, a sharer of the Nobel Prize in 1962 for his studies of the hemoglobin molecule.

Breathing could not keep us alive if it were not for the human hemoglobin molecule, a complex molecular masterpiece of design. The hemoglobin that is inside each of our 30 trillion red blood cells transports the oxygen from the lungs to the tissues throughout the body. Without hemoglobin, we would die almost instantly. But why?

see here :

http://reasonandscience.heavenforum.org/t1439-atp-synthase#2089

Question: How do hemoglobin molecules manage to pick up tiny oxygen molecules at the right time, hold them safely until the right time, and release them at the right time? Several amazing feats of molecular engineering are required. What use would there be to do this " shuttle " service, if cells and their energy requirement were not existing already?  Mitochondria, the energy factory in the cell, and ATP synthase rotary motors had to exist already, otherwise, hemoglobin would have no function. So had both not to be in place right from the beginning, and together? how could they have evolved separately?

Tiny Molecular “Taxis”

You might think of each hemoglobin molecule in a cell as a tiny four-door taxi, with room for exactly four “passengers.” This molecular taxi does not require a driver since it is riding inside a red blood cell, which could be described as a traveling container full of these hemoglobin molecules.

Question: what good would blood be for without red blood cells and hemoglobin? no use. (Channichthyidae fish

http://en.wikipedia.org/wiki/Channichthyidae

is an exception because of their low metabolic rates and the high solubility of oxygen in water at the low temperatures of their environment.)  What good would blood be for without the veins, and the heart, and the lungs, and the kidneys ? no use. So can we not say these are interdependent? did they not have to be there and fully developed right from the beginning ? each organ, and the blood? how could evolution manage to evolve all the organs and blood at the exact same time ? how could it manage to bring all parts together and interconnect them in the right manner? how could it manage to find all required multiple parts? isn't it rational to conclude that is a task, that evolution isn't able to do?

The journey for a hemoglobin molecule begins when red blood cells arrive at the alveoli of the lungs—the “airport.”

Alveoli are tiny organs that help our body parts get the oxygen that we breathe in and get rid of the carbon dioxide we don't need




As we inhale air into our lungs, the huge crowds of tiny recently arrived oxygen molecules start looking for a ride in a taxi. These molecules quickly diffuse into red blood cells, the “containers.” Oxygen in the lungs passes through the thin-walled blood vessels and into the red blood cells, where it binds to the hemoglobin, turning it into the bright red oxy-hemoglobin. The blood then passes around the body until it reaches cells and tissues which require oxygen to sustain their processes.At this point, the doors of the hemoglobin taxis within each cell are closed. However, it does not take long before a determined oxygen molecule in the bustling crowd squeezes in and takes a seat in a hemoglobin taxi.

Now, something very interesting happens. Inside the red cell, the hemoglobin molecule begins to change its shape. All four “doors” of the hemoglobin taxi begin to open automatically as the first passengers get in, which allows the remaining passengers to hop aboard more easily. This process, called cooperativity, is so efficient that in the time it takes to draw a single breath, 95 percent of the “seats” in all the taxis in a red blood cell are taken. Together the more than one-quarter of a billion hemoglobin molecules in a single red blood cell can carry about a billion oxygen molecules! Soon the red blood cell containing all these taxis is off to deliver its precious supply of oxygen to body tissues that need it.

Question: What came before: the body tissues, or the hemoglobin, blood, veins, heart, lungs etc. ? Body tissues without hemoglobin would have no oxygen supply. Hemoglobin without body tissues to supply with oxygen would have no function... Isn't there an interdependent relationship? Had both not to be there right from the beginning?

But, you might wonder, ‘What keeps oxygen atoms inside the cell from getting out prematurely?’

The answer is that inside each hemoglobin molecule, oxygen molecules attach to waiting atoms of iron. You have probably seen what happens when oxygen and iron get together in the presence of water. The result is usually iron oxide, rust. When iron rusts, the oxygen is locked up permanently in a crystal. So how does the hemoglobin molecule manage to combine and uncombine iron and oxygen in the watery environment of the red blood cell without producing rust?

Taking a Closer Look

To answer that question, let us take a closer look at the hemoglobin molecule. It is made up of some 10,000 atoms of hydrogen, carbon, nitrogen, sulfur, and oxygen that are carefully assembled around just 4 atoms of iron. Why do four iron atoms need so much support?

First, the four iron atoms are electrically charged and must be carefully controlled. Charged atoms, which are called ions, can do a lot of damage inside cells if they get loose. So each of the four iron ions is secured in the middle of a protective rigid plate.


Question: How did evolution manage to evolve the mechanism to secure the iron ions on the middle of the protective rigid plate ? trial and error ? Why should it do so and try ?

Next, the four plates are carefully fitted into the hemoglobin molecule in such a way that oxygen molecules can get to the iron ions but water molecules cannot get to them. Without water, rust crystals are unable to form.

Question : Isnt that a remarkable feat ? That seems far more likely the engeneering of a super intellect that manages these arrangements at atomic scales, rather than unguided random genetic mutation lucky accident event   providing such a highly elaborated mechanism, essential for many life forms.

By itself the iron in the hemoglobin molecule cannot bind and unbind oxygen. Yet, without the four charged iron atoms, the rest of the hemoglobin molecule would be useless. Only when these iron ions are perfectly fitted into the hemoglobin molecule can the transport of oxygen through the bloodstream occur.

Releasing the Oxygen

https://www.youtube.com/watch?v=WXOBJEXxNEo



As a red blood cell leaves the arteries and moves into the tiny capillaries deep in the body tissues, the environment around the red blood cell changes. Now the environment is warmer than in the lungs, and there is less oxygen and more acidity from the carbon dioxide surrounding the cell. These signals tell the hemoglobin molecules, or taxis, inside the cell that it is time to release their precious passengers, oxygen.

When the oxygen molecules get out of the hemoglobin molecule, it changes its shape once more. The change is just enough to “close the doors” and leave the oxygen outside, where it is most needed. Having the doors shut also prevents the hemoglobin from transporting any stray oxygen on the way back to the lungs. Instead, it readily picks up carbon dioxide for the return trip.

Question: How did it " learn " to bring carbon dioxide back to the lungs ?

Soon the deoxygenated red blood cells are back in the lungs, where the hemoglobin molecules will release the carbon dioxide and be recharged with life-sustaining oxygen—a process that is repeated many thousands of times during a red blood cell’s life span of about 120 days.

Clearly, hemoglobin is no ordinary molecule. It is, as stated at the beginning of this article, “a giant molecule of vast complexity.” Surely, this is awe inspiring, brilliant and meticulous microengineering that makes life possible, which demands a adequate explanation of how it came to be.


The biosynthesis pathway of hemoglobin is irreducible complex

Hemoglobin is a globular molecule which is made up of four subunits. Each subunit contains heme (an iron-containing porphyrin derivative). Each heme molecule is conjugated to a polypeptide which is called the globin. In each hemoglobin molecule there are 4 chains of polypeptides (2 pairs). In hemoglobin A, which is normal adult human hemoglobin, the two polypeptides are called α chains and the other two, β chains.






How is the heme molecule attached to the globin protein in the synthesis process?

http://www.quora.com/How-is-the-heme-molecule-attached-to-the-globin-protein

The answer is coordinate-covalent bonds, along with other forces.

Hemoglobin is a globular molecule which is made up of four subunits. Each subunit contains heme (an iron-containing porphyrin derivative). Each heme molecule is conjugated to a polypeptide which is called the globin. In each hemoglobin molecule there are 4 chains of polypeptides (2 pairs). In hemoglobin A, which is normal adult human hemoglobin, the two polypeptides are called α chains and the other two, β chains.

http://www.madsci.org/posts/archives/2006-11/1163441912.Bc.r.html

Haem biosynthesis and haemoglobin assembly are very complicated biochemical pathways and scientists still do not understand fully all of the steps.

Synthesis of Hemoglobin

http://www.madsci.org/posts/archives/2006-11/1163441912.Bc.r.html

Hemoglobin (Hb) is synthesized in a complex series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol. Synthesis starts in the mitochondria because they supply a molecule called succinyl-CoA, which is a building block for the haem. However when the haem is partially built, it is moved out into the cytoplasm. Some more reactions occur, then the molecule moves back to the mitochondrion where it is finished and the iron is added.

That seems very complex - why does the synthesis occur in 2 locations? The answer is that it allows the cell to regulate haem synthesis. The mitochondrial enzymes required for haem synthesis have to be imported into the mitochondrion from the cytoplasm, where they are made on ribosomes. If the cell has high levels of haem and doesn't need to make any more, the haem actually inhibits this import process. There is a second level of regulation too - if haem levels are high in the cytoplasm, transcription of the genes for haem synthesis is also inhibited. So by using 2 locations for synthesis, the cell can fine-tune the regulation of haem production. Pretty clever hey?

Question: how did the cell learn to fine tune haem production ?

Chemical steps in the formation of hemoglobin:

2α Ketoglutonic acid(it comes from creb's cycle) + 2 glycine → pyrrole
4 pyrrole → protoporphyrine
porphyrine + Fe+ → heme
4 heme + 4 polypeptide chain(2α + 2β → 1 hemoglobin molecule

http://en.wikipedia.org/wiki/Porphyrin

follwing the pathway :





Globin synthesis

Gene Duplication and the Origin of Novel Biological Information: A Case Study of the Globins

http://www.uncommondescent.com/evolution/gene-duplication-and-the-origin-of-novel-biological-information-a-case-study-of-the-globins/

there are at least five difficulties associated with the evolution of the globins by virtue of gene duplication and divergence. These are:

   The question of the adaptive value of proposed intermediates.
   Complementary changes involving the regulation of gene expression.
   The time constraints associated with finding a selectable function for the duplicated copy.
   The fragility problem.
   Problems of convergence.

http://sickle.bwh.harvard.edu/hbsynthesis.html

Hemoglobin synthesis requires the coordinated production of heme and globin. Heme is the prosthetic group that mediates reversible binding of oxygen by hemoglobin. Globin is the protein that surrounds and protects the heme molecule.

Question : how could evolution coordenate its production ?

Heme is synthesized in a complex series of steps involving enzymes in the mitochondrion and in the cytosol of the cell

Question: How did these complex series of steps evolve?  how and why did the involving enzymes evolve? The enzymes, the mitochondrion, and the cytosol had to be present, in order to synthesize hemoglobin.

The synthesis of heme is a complex process that involves multiple enzymatic steps. The process begins in the mitochondrion with the condensation of succinyl-CoA and glycine to form 5-aminolevulinic acid. A series of steps in the cytoplasm produces coproporphrynogen III, which re-enters the mitochondrion. The final enzymatic steps produce heme.

Following the enzymes involved :

ALA synthase

http://en.wikipedia.org/wiki/Aminolevulinic_acid_synthase

ALA synthase (EC 2.3.1.37), or ALAS, catalyzes the synthesis of D-Aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes, cobalamins and chlorophylls. ( therefore its not unique in this pathway.  co-option from other biological systems is theoretically possible )

ALA dehydratase

http://en.wikipedia.org/wiki/Porphobilinogen_synthase

All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen as a common precursor. ( therefore its not unique in this pathway.  co-option from other biological systems is theoretically possible )

PBG deaminase

http://en.wikipedia.org/wiki/Porphobilinogen_deaminase

Porphobilinogen deaminase is involved in the third step of the heme and chlorophyll biosynthetic pathway.

Uroporphyrinogen III synthase

http://ghr.nlm.nih.gov/gene/UROS

This enzyme is involved in the production of a molecule called heme. ( therefore its unique in this pathway. No co-option from other biological systems is possible )

Uroporphyrinogen III decarboxylase

http://en.wikipedia.org/wiki/Uroporphyrinogen_III_decarboxylase

This gene encodes the fifth enzyme of the heme biosynthetic pathway. ( therefore its unique in this pathway. No co-option from other biological systems is possible )

Coproporphyrinogen III oxidase

http://en.wikipedia.org/wiki/Coproporphyrinogen_III_oxidase

It is an enzyme involved in the sixth step of porphyrin metabolism it catalyzes the oxidative decarboxylation of coproporphyrinogen III to proto-porphyrinogen IX in the haem and chlorophyll biosynthetic pathways. ( therefore its just used in one other pathway ( chlorophyll )


Protoporphyrinogen oxidase

http://en.wikipedia.org/wiki/Protoporphyrinogen_oxidase

Protoporphyrinogen oxidase (EC 1.3.3.4) is an enzyme that is responsible for the seventh step in the biosynthesis of protoporphyrin IX. This porphyrin is the precursor to hemoglobin, the oxygen carrier in animals, and chlorophyll, the dye in plants. ( therefore its unique in this pathway. No co-option from other biological systems is possible )


Ferrochelatase Mitochondrion

http://en.wikipedia.org/wiki/Ferrochelatase

Ferrochelatase (FECH, protoheme ferrolyase) is an enzyme that catalyzes the terminal (eighth) step in the biosynthesis of heme, converting protoporphyrin IX into heme. ( therefore its unique in this pathway. No co-option from other biological systems is possible )


The PBG deaminase enzyme

http://en.wikipedia.org/wiki/Porphobilinogen_deaminase

Porphobilinogen deaminase is involved in the third step of the heme biosynthetic pathway. No other use is mentioned,  therefore we can assume its uniquely used in this pathway.
This enzyme catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane while releasing four ammonia molecules.

Structure and function
Functionally, porphobilinogen deaminase catalyzes the loss of ammonia from the porphobilinogen monomer (deamination) and its subsequent polymerization to a linear tetrapyrrole, which is released as hydroxymethylbilane:



The first step is believed to involve an E1 elimination of ammonia from porphobilinogen, generating a carbocation intermediate (1).[6]

The second step : This intermediate is then attacked by the dipyrrole cofactor of porphobilinogen deaminase, which after losing a proton yields a trimer covalently bound to the enzyme (2).

The third step This intermediate is then open to further reaction with porphobilinogen (1 and 2 repeated three more times). Once a hexamer is formed, hydrolysis allows hydroxymethylbilane to be released, as well as cofactor regeneration (3)

The fourth step Once a hexamer is formed, hydrolysis allows hydroxymethylbilane to be released, as well as cofactor regeneration

What co-factor are we talking about? let's see.

Porphobilinogen deaminase, dipyrromethane cofactor binding site (IPR022419)
Short name: Porphobilin_deaminase_cofac_BS

http://www.ebi.ac.uk/interpro/entry/IPR022419

Description
This entry represents the region around cysteine residues that is conserved in porphobilinogen deaminases from various prokaryotic and eukaryotic sources. The sulfur atom of this cysteine residue has been shown in the Escherichia coli enzyme (gene hemC) to be bound to the dipyrromethane cofactor [PMID: 3196304]. Porphobilinogen deaminase covalently binds a dipyrromethane cofactor to which the PBG subunits are added in a stepwise fashion. Porphobilinogen deaminase has a three-domain structure. Domains 1 (N-terminal) and 2 are duplications with the same structure, resembling the transferrins and periplasmic binding proteins. The dipyrromethene cofactor is covalently linked to domain 3 (C-terminal), but is bound by extensive salt-bridges and hydrogen-bonds within the cleft between domains 1 and 2, at a position corresponding to the binding sites for small-molecule ligands in the analogous proteins [PMID: 1522882]. The enzyme has a single catalytic site, and the flexibility between domains is thought to aid elongation of the polypyrrole product in the active-site cleft of the enzyme.

Questions: how did gene duplication, followed by random mutations and natural selection figure out to produce  the  PBG deaminase enzyme,, used as far as science knows, exclusively in this pathway, so no co-option possible? -  that would produce this complex reaction, ( which is just the third in the whole pathway of total 8 steps )  consisting in 4 highly coordinated, ordered, sequenced and complex steps, forming a geometrically correct tetrapyrrole, and repeat the first two steps in total 4 times? How did evolution be capable to produce the right genetic code and informational sequence?  How did evolution figure out to program the release of the hydroxymethylbilane enzyme at the right time, after the product, the linear hydroxymethylbilane was catalyzed, and while releasing four ammonia molecules?

1. Werner Gitt, Without excuse, page 308
2. http://www.sciencedirect.com.https.sci-hub.hk/science/article/pii/S0005272812010407

http://www.uncommondescent.com/evolution/gene-duplication-and-the-origin-of-novel-biological-information-a-case-study-of-the-globins/

red blood cells contain hemoglobin, which is responsible for carrying oxygen to every cell in the body.1 Hemoglobin is a complex protein that has two pairs of chains (referred to as alpha and beta) which bind to the red-pigmented molecule known as heme. As Blakemore and Jennett described: “In most mammals, adult hemoglobin (hemoglobin A) comprises two unlike pairs of chains of amino acids, or globin chains, called α and β, each of which is folded round one iron-containing heme molecule, to which oxygen can bind” (p. 85). This configuration allows hemoglobin to transport four molecules of oxygen. Given the added surface area from the anucleated biconcave disc, each cell would contain “about 280,000,000 molecules of hemoglobin” (see “Cardiovascular System,” 2004). What are the odds that this engineering accomplishment happened by random chance? Consider that an evolutionary origin of hemoglobin would require a minimum of 120 mutations to convert an alpha chain to a beta. At least 34 of those changes require changeovers in 2 or 3 nucleotides. Yet, if a single nucleotide change occurred through mutation, the result would ruin the blood and kill the organism. Simply put, evolution cannot explain the existence of hemoglobin molecules in the circulatory system of humans.

1) http://www.apologeticspress.org/ApPubPage.aspx?pub=1&issue=571&article=450
http://evoillusion.org/3091-2/

http://www.gloriadeilcms.org/faq3.html

proposals of evolution :

http://www.news.cornell.edu/stories/2013/02/ct-scans-help-answer-question-fish-lung-evolution

The researchers hypothesize that this evolutionary change occurred either by the loss of respiration or by dorsal shifts in the anatomical structures of these fishes.


nice try though.....

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543078/


http://www.asa3.org/evolution/irred_compl.html

Sea lamprey globin evidences what might be the next intermediate stage. Sea lampreys have a separate myoglobin for oxygen storage and a hemoglobin-like molecule for oxygen transport. Lamprey hemoglobin is dimeric rather than tetrameric. It does display cooperative oxygen binding, though. Lamprey deoxyglobin forms dimers which dissociate upon oxygen binding. The dimer contacts are in exactly the region of the molecule where one alpha-beta dimer interacts with the other alpha-beta dimer. This is the region that modulates the 15° rotation and the cog-slipping effect that was described above. Murray Goodman and co-workers cite evidence from their sequence comparisons that suggest that mutations accumulated in this region of the molecule at four times the rate for the molecule as a whole during the evolution of this new function. Clearly, cooperativity of oxygen binding is a consequence of dimerization. But dimer formation is the result of greasy patches on the surface of the protein, which could well have arisen by a few amino acid substitutions (or even one as is the case in deoxyhemoglobin S fibers in sickle-cell anemia). Dimer formation would have been a Darwinian pre-adaptation to the evolution of cooperative oxygen binding.

The next step in hemoglobin evolution is the result of a gene duplication of the ancestral hemoglobin-like gene into the modern alpha and beta globin genes. Again, the original oxygen transporting function could be preserved, while mutations acted upon the second copy of the gene. The very similar but slightly different version of the globin allowed for the formation of the alpha beta dimer which upon interaction with another alpha-beta dimer allowed the preservation of the tetramer structure even upon oxygenation. Again Goodman's group believe that their sequence comparison data suggests that the alpha-beta dimer interface accumulated mutations at nearly twice the rate for the whole molecule during the evolution of this new function. Again, the gene duplication event and the alpha-beta dimer formation are pre-adaptations to the formation of the complex tetramer.

nice example about how helpless naturalistic explanations are. Just so stories at their best.


http://mbe.oxfordjournals.org/content/22/12/2343.full

Abstract

Heme biosynthesis represents one of the most essential metabolic pathways in living organisms, providing the precursors for cytochrome prosthetic groups, photosynthetic pigments, and vitamin B12. Using genomic data, we have compared the heme pathway in the diatom Thalassiosira pseudonana and the red alga Cyanidioschyzon merolae to those of green algae and higher plants, as well as to those of heterotrophic eukaryotes (fungi, apicomplexans, and animals). Phylogenetic analyses showed the mosaic character of this pathway in photosynthetic eukaryotes. Although most of the algal and plant enzymes showed the expected plastid (cyanobacterial) origin, at least one of them (porphobilinogen deaminase) appears to have a mitochondrial (α-proteobacterial) origin. Another enzyme, glutamyl-tRNA synthase, obviously originated in the eukaryotic nucleus. Because all the plastid-targeted sequences consistently form a well-supported cluster, this suggests that genes were either transferred from the primary endosymbiont (cyanobacteria) to the primary host nucleus shortly after the primary endosymbiotic event or replaced with genes from other sources at an equally early time, i.e., before the formation of three primary plastid lineages. The one striking exception to this pattern is ferrochelatase, the enzyme catalyzing the first committed step to heme and bilin pigments. In this case, two red algal sequences do not cluster either with the other plastid sequences or with cyanobacterial sequences and appear to have a proteobacterial origin like that of the apicomplexan parasites Plasmodium and Toxoplasma. Although the heterokonts also acquired their plastid via secondary endosymbiosis from a red alga, the diatom has a typical plastid-cyanobacterial ferrochelatase. We have not found any remnants of the plastidlike heme pathway in the nonphotosynthetic heterokonts Phytophthora ramorum and Phytophthora sojae.

That argument just throws the problem back to the question, how did the chlorophyll biosynthesis pathway evolve ??

Evolution of Hemoglobin and Its Genes

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543078/pdf/cshperspectmed-HMG-a011627.pdf


Organization, evolution and regulation of the globin genes

http://www.bx.psu.edu/~ross/pubs/OrgEvolGlbGenes_DisordersHb_wFigs.htm


HEMOGLOBINS FROM BACTERIA TO MAN: EVOLUTION OF DIFFERENT PATTERNS OF GENE EXPRESSION

http://biology.hunter.cuny.edu/molecularbio/Class%20Materials%20Fall%202013%20Biol203/Evolution%20of%20Hemoglobins%20review.pdf

the ancestral heme protein gene  is cytochrome 562b.


http://www.freerepublic.com/focus/news/1504645/replies?c=98

To set the record straight: The second and more important point is that, while the paper is very interesting, it doesn't address irreducible complexity. Either Miller hasn't read what I said in my book about metabolic pathways, or he is deliberately ignoring it. I clearly stated in Darwin's Black Box metabolic pathways are not irreducibly complex (Behe 1996) (pp. 141-142; 150-151), because components can be gradually added to a previous pathway. Thus metabolic pathways simply aren't in the same category as the blood clotting cascade or the bacterial flagellum.
Underlines mine

You appear to be under the misapprehension that the blood clotting cascade is a metabolic pathway, or suffering under some other confusion.

http://www.reasons.org/articles/origin-of-hemoglobins-a-repeated-problem-for-biological-evolution

Evolutionary biologists believe that hemoglobin originated from an ancestral globin molecule through the process of gene duplication (in which a number of globin gene copies were generated through chance events). These duplicated genes were then co-opted to generate an oxygen transport protein (hemoglobin). Once it originated, this protein became encapsulated within erythrocytes (red blood cells). These scientists claim that this encapsulation provided an evolutionary advantage because passive diffusion of oxygen in the blood is not sufficient to sustain the high metabolic demands of large complex creatures.

http://www.americanscientist.org/my_amsci/restricted.aspx?act=pdf&id=3023788974733

Hemoglobin—the oxygen-transport protein that gives blood its red color—got its start at about the time life originated on earth, nearly four billion years ago.

https://designmatrix.wordpress.com/2009/06/11/front-loading-blood/

This protoglobin is thought to be present in organisms possibly as far back as the Last Universal Common Ancestor, or LUCA, the source of all life on Earth. LUCA is believed to have been a metabolically “flexible” single-celled organism with the ability to utilize oxygen for energy before free oxygen even existed in the air, thus preceding oxygenic photosynthesizers. The idea that an organism existed with the capacity to “breathe” O2 before there was a real need to, however, goes against the textbook viewpoint [45]. In his recent book [9], Nick Lane argues that LUCA likely made use of a hemoglobin-like protein to manage oxygen homeostasis and an antioxidant enzyme like superoxide dismutase (SOD) to protect itself. This hemoglobin would not have to deal with much oxygen at all, but rather very low levels of oxygen, perhaps similar to the role of leghemoglobin in nitrogen-fixing bacteria.

The Porphobilinogen  deaminase enzyme involved in the third step of the heme biosynthetic pathway



http://www.uniprot.org/uniprot/P08397

EC 2.5.1.61

Older sources categorize it under EC 4.3.1.8

Porphobilinogen deaminase (PBGD) is involved in the third step of the heme and chlorophyll biosynthetic pathway.This enzyme  catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane while releasing four ammonia molecules. 2) It assembles the four rings of PBG in a stepwise fashion in which the pyrrole ring A is first bound to the deaminase followed by rings B, C and finally D . The dipyrromethane cofactor  ( A cofactor is a non-protein chemical compound that is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations. ) , which arises from the autocatalytic coupling of two molecules of PBG, is covalently linked to the enzyme. The cofactor functions as a primer to which the four substrate molecules are sequentially attached but is not itself incorporated into the product, hydroxymethylbilane.


As we will see, this enzyme  is highly  complexity and specified in its structure, using co-factors in order to catalyze the first and second step of heme and chlorophyll biosynthesis.  

Structure and function
Functionally, porphobilinogen deaminase catalyzes the loss of ammonia from the porphobilinogen monomer (deamination) and its subsequent polymerization to a linear tetrapyrrole, which is released as hydroxymethylbilane 3)



The first step is believed to involve an E1 elimination of ammonia from porphobilinogen, generating a carbocation intermediate

The second step : This intermediate is then attacked by the dipyrrole cofactor of porphobilinogen deaminase, which after losing a proton yields a trimer covalently bound to the enzyme .

The third step This intermediate is then open to further reaction with porphobilinogen (1 and 2 repeated three more times)

The fourth step Once a hexamer is formed, hydrolysis allows hydroxymethylbilane to be released, as well as cofactor regeneration


The reaction catalysed by PBGD involves the formation of preuroporphyrinogen, a linear tetrapyrrole (bilane), by the extension of an enzyme-bound DPM (dipyrromethane) cofactor that acts as a reaction primer 4)

Question: how could evolution have achieved the arise of this complex function ? It had to program into the genome the specification for the production of the co-factor molecule, and its function of extension binding of intermediates during the catalytic reaction at the right place, at the right moment, in the right sequence.   1)


Porphobilinogen deaminase, dipyrromethane cofactor binding site (IPR022419)
Short name: Porphobilin_deaminase_cofac_BS

Description
This entry represents the region around a cysteine residues that is conserved in porphobilinogen deaminases from various prokaryotic and eukaryotic sources. The sulphur atom of this cysteine residue has been shown in the Escherichia coli enzyme (gene hemC) to be bound to the dipyrromethane cofactor [PMID: 3196304]. Porphobilinogen deaminase covalently binds a dipyrromethane cofactor to which the PBG subunits are added in a stepwise fashion. Porphobilinogen deaminase has a three-domain structure. Domains 1 (N-terminal) and 2 are duplications with the same structure, resembling the transferrins and periplasmic binding proteins. The dipyrromethane cofactor is covalently linked to domain 3 (C-terminal), but is bound by extensive salt-bridges and hydrogen-bonds within the cleft between domains 1 and 2, at a position corresponding to the binding sites for small-molecule ligands in the analogous proteins [PMID: 1522882]. The enzyme has a single catalytic site, and the flexibility between domains is thought to aid elongation of the polypyrrole product in the active-site cleft of the enzyme. 5)

Questions : how did gene duplication, followed by random mutations and natural selection figure out to produze  the  PBG deaminase enzyme,, used as far as reported, exclusively in this path way, so no co-option possible ? -  that would produce this complex reaction, ( which is just the third in the whole heme and chlorophyll biosynthesis pathway of total 8 and 17 steps )  consisting in 4 highly coordenated , ordered, sequenced and complex steps, forming a geometrically correct tetrapyrrole, and repeat the first two steps in total 4 times ? and furthermore use co-enzyme molecules ? Could evolution be a feasable mechanism ? How did evolution be capable to produce  the right genetic code and informational sequence ? The genetic code uses average over 300 thousand nucleotides in the sequence.   How did evolution figure out to program the release at the end of the process of the hydroxymethylbilane enzyme from the reaction at the right time, after the linear hydroxymethylbilane product is catalized, and while releasing four ammonia molecules ?

PBGD enzymes possesses several novel features. First, the initial protein translation product is an apoenzyme that has the ability to construct its own DPM cofactor using two of the pyrrole units of preuroporphyrinogen .

Question: How did it achieve the hability to do so ? evolution, or design ?

Secondly, each of the four substrate condensation steps occurs at a single catalytic site  and the enzyme is therefore able to translocate the growing polypyrrole chain to vacate the substrate-binding site for the next incoming substrate.

Question: How did it achieve the hability to do this in a coordinated, ordered and systematic way ? evolution, or design

Thirdly, the enzyme can ‘count’ precisely to four and terminate the polymerization reaction by hydrolysis when the hexapyrrole chain (ES4) has been assembled 6)


Question: What does explain this feat better, design or evolution ? lets remember, that evolution has only mutation and natural selection on hand as mechanism to provide new functions . Heme or chlorophyll can only be produced, if the PBGD enzyme  if fully developed and exercising its function. How did evolution be able to provide the right instructions in order of  the enzyme  to count precisely to four and how did it get this feat to be able to instruct  to terminate the polimerization reaction  at the right moment?

Porphobilinogen deaminase gene structure
The PBGD gene comprises 15 exons encoded within a 10-kilobase (kb) region of chromosome 11q23.3 7)

The porphobilinogen deaminase gene

The gene coding for PBGD is assigned to chromosome 11q24. The size of the gene is 10 kb of which 1.3 kb represents coding sequence. The genomic sequence is divided into 15 exons ranging from 39 and 438 bp and 14 introns ranging from 87 to 2913 bp (Figure 2.4.).

The mRNA of the  isoform contains exons 1 and 3 to 15 coding for an enzyme of 361 amino acids

More recently, it has been shown that the hemoglobin gene precedes even the prokaryote/eukaryote split. 9)

Question: If the hemoglobin gene is that ancient, did it have enough time to evolve the complexity of the pathway, all enzymes and co factor molecules , and provide all the diverse instructions demonstrated here ?


The evolution of hemoglobin. 10)

e. It appears that the apparatus that sequesters oxygen in cells, possibly to protect them, is almost identical to the one that, in different contexts, exploits oxygen for its energy-generating potential. At first this apparatus was quite primitive, probably limited to a caged metal atom capable of binding oxygen or tearing away its electrons, which are used in metabolism. But this basic chemical apparatus grew increasingly complex through time and evolution. At some point the metal atom was fixed inside a kind of flat molecular cage called a porphyrin ring, and later that porphyrin ring became embedded in larger organic compounds called proteins. These organic compounds themselves became increasingly varied through time and evolution.

Question: Isnt that typical superfical pseudoscience, based on just so guesswork without a shred of evidence to back up the claim ? Where is the detailled explanation about how the extremely complex biosynthesis pathway could have started and evolved ? That explanation is equal to a NO explanation..... just for the guillible without critical thinking. Yes, there is good reason to be skeptic towards that kind of information and assertions and guesswork.


Hemoglobins Connect Almost All Life on the Planet
We normally think of hemoglobin in the context of our own blood, comprising about 85% of the dry weight of red blood cells and a whopping 35% wet weight. For a protein, this is extremely concentrated. What surprises most people is the ubiquitousness and varied functions of hemoglobins in not just the animal world. Plants use hemoglobins, as do fungi, protists and bacteria. The gene encoding hemoglobin is thus very old, going back to the ancestor common to essentially all life on this planet. In fact, the only group for which hemoglobins have not been found are within the kingdom Archaea, considered to be the living relatives of the most ancient form of life we know about on this planet.

A great deal of speculation has gone into how hemoglobins arose in the first place. Perhaps it initially evolved in order to help protect the cell from the continually rising amounts of the toxin known as oxygen from photosynthetic organisms. Once cells began to use oxygen in respiratory processes, hemoproteins could act as electron-transfer agents or to scavenge oxygen for respiration. Gene duplications with mutation would allow other redox agents (like the cytochrome b molecules) to evolve from the ancestral hemoprotein gene. Once multicellular organisms arose, hemoglobins could then evolve into their current function of oxygen transporers. At an early stage of evolution, it has been proposed that worm-like animals had large polymeric aggreggations of hemoglobin subunits circulating through primitive circulatory systems. Next would be monomeric hemoglobin in blood cells functioning as oxygen storage. 9)


1) http://www.ncbi.nlm.nih.gov/pubmed/3079571
The cofactor is involved in the binding of intermediates during the catalytic reaction but is not incorporated into the product preuroporphyrinogen
2) http://en.wikipedia.org/wiki/Porphobilinogen_deaminase
3) http://scripts.iucr.org/cgi-bin/paper?S0907444912052134
4) http://www.biochemj.org/bj/420/0017/4200017.pdf
5) http://www.ebi.ac.uk/interpro/entry/IPR022419
6) http://www.biochemj.org/bj/420/0017/4200017.pdf
7) http://www.bloodjournal.org/content/bloodjournal/97/3/815.full.pdf?sso-checked=true
8 ) http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/mustajoki/review.html
9) https://shamelesslyatheist.wordpress.com/2008/10/11/evolution-hemoglobin/
10) http://zoology.wisc.edu/courses/611/Part2/Readings/5The_Evolution_of_Hemoglobin.pdf

Technological Ingenuity in Red Blood Cells 2

http://reasonandscience.heavenforum.org/t1322-the-amazing-hemoglobin-molecule#5300

Each mm3 (= 1 ul = 1 microliter) of our blood contains five million red blood cells; so there are 150 million of them in each drop of blood. These highly specialized cells perform functions vital to life.
• Throughout their 120-day lifetime, while circulating through the lungs, they are refueled with oxygen 175,000 times, while simultaneously offloading carbon dioxide, the waste product of oxidation.
• Red blood cells are so tiny that they can squeeze through narrow capillaries to reach every part of the body.
• Our body produces two million new red cells every second and each cell is rich in hemoglobin, a remarkably complex chemical compound.

Hemoglobin is used for transporting oxygen, even during development of the embryo. Up to about the third month of pregnancy, the embryo's oxygen needs are distinctly different from those in the ensuing fetal stage, which are different again from the needs of the infant and adult. All three stages— embryo, fetus and adult—require the production of chemically different forms of hemoglobin. Shortly before birth, for example, the body's 'factories' start switching to top production mode of the third (adult) type of hemoglobin. These three types of hemoglobin could not have arisen by trial-and-error evolutionary processes because none of the other mutant forms of the hemoglobin molecule could carry enough oxygen and would thus be deadly. Even if the right forms of hemoglobin were to somehow arise to supply the first two stages, but without the genetic coding to produce the third form, the outcome would still be certain death. Each of these three stages of our development requires fundamentally different DNA coding to produce each of the three different hemoglobin molecules. Further, each set of different DNA coding, and its biomachinery that synthesizes the hemoglobin molecules must be switched on and off at the right point in time.

Where did such a complex system of information-controlled machinery come from? All conceivable evolutionary explanations fail miserably because any partially completed transitional stage required by evolution would not permit the organism to survive. The whole complex of information and machinery must be present and functional from the start.  In each case, the organisms 'on the way' to their completed state would not have been able to survive. A more obvious explanation is that this information-controlled machinery was initially complete—something only possible if a wise Creator conceived and made everything fully functional in the beginning.

Technological Ingenuity in Red Blood Cells
Expression of globin genes is tightly regulated. Hemoglobin gene expression is restricted to erythroid cells. 1
Production of different forms of hemoglobin at progressive developmental stages is widespread in vertebrates and beyond, and studies of hemoglobin switching are pursued in several non-human species as models of the process in humans.

Evolution of Hemoglobin and Its Genes
All species examined make embryonic-specific hemoglobins in primitive erythroid cells derived from the yolk sac, some species make a fetal-specific form in the liver, and all species produce an “adult” hemoglobin in erythroid cells produced in the bone marrow (Maniatis et al. 1980; Karlsson and Nienhuis 1985). 3





1.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543078/
2. Werner Gitt, without excuse, page 307
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543078/pdf/cshperspectmed-HMG-a011627.pdf

WITHOUT EXCUSE  WERNER GITT, PH.D., page 307
Our body produces two million new red cells every second and each cell is rich in hemoglobin, a remarkably complex chemical compound.

Hemoglobin is used for transporting oxygen, even during development of the embryo. Up to about the third month of pregnancy, the embryo's oxygen needs are distinctly different from those in the ensuing fetal stage, which are different again from the needs of the infant and adult. All three stages— embryo, fetus and adult—require the production of chemically different forms of hemoglobin. Shortly before birth, for example, the body's 'factories' start switching to top production mode of the third (adult) type of hemoglobin. These three types of hemoglobin could not have arisen by trial-and-error evolutionary processes because none of the other mutant forms of the hemoglobin molecule could carry enough oxygen and would thus be deadly. Even if the right forms of hemoglobin were to somehow arise to supply the first two stages, but without the genetic coding to produce the third form, the outcome would still be certain death. Each of these three stages of our development requires fundamentally different DNA coding to produce each of the three different hemoglobin molecules.

Further, each set of different DNA coding, and its biomachinery that synthesizes the hemoglobin molecules must be switched on and off at the right point in time. Where did such a complex system of information-controlled machinery come from? All conceivable evolutionary explanations fail miserably because any partially completed transitional stage required by evolution would not permit the organism to survive. The whole complex of information and machinery must be present and functional from the start.